Colorectal cancer (CRC) is the second leading cause of cancer death in the United States and the fourth most commonly diagnosed cancer. There is increasing recognition of diet-induced modulation of inflammatory responses as being central to the processes of human carcinogenesis. The argument for this stems from the observations that pro-inflammatory states are closely linked to tumor promotion. The consumption of the anti- inflammatory dietary constituents curcumin, which is a component of the Indian spice currie, and quercetin, a flavonoid present in various fruits and vegetables, have been associated with reduced CRC risk. Such components of diet are generally known to have a much wider safety margin with chronic use than are anti- inflammatory drugs, which make them more viable candidates to aid in cancer prevention. While a number of studies have examined the effects of dietary supplements on inflammation in cancer, none have specifically examined the role of tissue macrophages (Ms), primary mediators of inflammation, on these effects. Further, few have examined combinations of dietary supplements on the biological mechanisms of carcinogenesis. The overarching goal of this proposed project is to 1) determine the independent and combined effects of the anti-inflammatory dietary constituents curcumin and quercetin on CRC progression, and 2) to determine whether these benefits result from a reduction in M-induced inflammation. It is clear that M-induced inflammation plays an important part in the initiation and progression of CRC, and it may also be responsible for various sickness behaviors like fatigue, lack of appetite, and body wasting that can drastically decrease quality of life in CRC patients. A substantial proportion and perhaps the majority of CRCs are associated with non-genetic factors, such as inadequate and/or over nutrition, which can amplify inflammation in a number of ways. An independent, additive or synergistic effect of the anti-inflammatory dietary constituents curcumin and quercetin may be of critical public health significance in the prevention of CRC. The specific aims of this project are to 1) to elucidate the combined effects of curcumin and quercetin on M infiltration, inflammation, CRC progression and host survival and 2) to more specifically determine the role of M-induced inflammation on these effects. A mouse transgenic model of CRC will be used to determine the independent and combined effects of curcumin and quercetin on inflammatory processes, M infiltration, tumor progression and host survival at specific stages of CRC (e.g. prevention versus treatment). Furthermore, we will use M manipulation techniques to evaluate whether Ms are an important common pathway of the effects of curcumin and quercetin on inflammation, tumor progression and host survival. The overall goal of this project is to develop a clinically testable regimen to delay and/or prevent CRC and to begin to understand if the mechanisms of the effects are related to M infiltration and subsequent inflammation that could be targeted by further behavioral and or medical treatment. PUBLIC HEALTH RELEVANCE: The dietary compounds curcumin, a component of the Indian spice curry, and quercetin, a component of some fruits and vegetables, have anti-inflammatory properties and have been associated with reduced colon cancer risk. These compounds modify inflammatory processes which may be linked with the formation and development of tumors. The goal of the proposed study is to investigate the independent and combined effects of curcumin and quercetin on the progression of colon cancer and to determine if these effects result from a reduction in macrophage-induced inflammation.